Earlier we introduced the concept of toll-like receptor mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation was demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Unnatural (+)-Naltrexone and (+)-naloxone, long thought to be inert compounds, act as functional antagonists of Toll-like receptor 4 (TLR4) and have been shown to reverse neuropathic pain in rat studies. With the goal of identification of novel TLR4 antagonists, we designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities in vitro by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro3,2-eisoquinolin-7(7aH)-one, 1j) showed 75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 M/1.4 M) was among the best of the new analogs. This compound was active in vivo; it significantly increased and prolonged morphine analgesia. We have also studied the role of TLR4 in the neurological deficit seen in the majority of survivors of cardiac arrest (CA) after cardiopulmonary resuscitation (CPR). Most of these individuals show signs of decreased memory or executive cognitive function. Such memory impairment may be due to hippocampal CA1 neuronal death involving classical microgliosis in the CA1 region yet the role of the key activation receptor TLR4 has not been previously investigated for such neuronal death after CA/CPR. We have now shown that (+)-naltrexone is neuroprotective after CA/CPR in a mouse model. TLR4 blockade was associated with decreased expression of markers for microglial/macrophage activation and T cell and B cell infiltration, as well as decreased pro-inflammatory cytokine levels. Thus, (+)-naltrexone and other TLR4 antagonists may represent a novel therapeutic strategy to alleviate the burden of memory or executive cognitive function impairment after CA/CPR.